Targeting anticancer drugs to the intestinal lymphatic system for improved treatment of cancer

The lymphatic system plays an important role in the pathophysiology of cancer as it can be both a site for the primary cancer and the major route of metastasis. Involvement of the intestinal lymphatic system is a predominant finding in 30-50% of the patients with non-Hodgkin’s lymphomas. Intestinal lymphatic system also provides the primary transportation route for the spreading of tumour cells from the gastrointestinal tract and other cancers from the pelvic region, therefore it is a critical pathophysiological compartment in cancer metastasis. It is challenging for systemic chemotherapy to specifically target the tumour in the lymphatics as only limited amount of drug can be distributed from the systemic circulation into the lymphatic system.
Discovery and development of antineoplastic agents with potential for intestinal lymphatic absorption following oral administration could significantly contribute towards improvement of survival rates of these patients. The distribution of drugs to the lymphatic system after oral administration is determined mainly by the association of drugs with large lipoproteins (chylomicrons) in the enterocytes. Therefore, by designing derivatives of anticancer agents that possess the necessary physicochemical properties for enhanced association with CM, we will be able to develop anticancer agents that target the lymphatic system. With chemical modification of existing or new anticancer agents, and lipid-based formulations that facilitate lymphatic transport, the concentration of such agents in the lymph can be achieved at levels of up to 500-fold higher than in plasma. Over the last several years substantial in vitro and in vivo preliminary data have been generated in our laboratory. These data demonstrate the efficient lymphatic targeting of anticancer compounds bexarotene and retinoic acid using prodrug approach.
Therefore, the aims of this PhD project will be focused on design and synthesis of prodrugs of additional (more novel and active) anticancer compounds, assessment of the intestinal lymphatic transport of these compounds, and assessment of the efficacy of the lymphatic targeting approach in cells and in animal models.